We studied the effects of the potent inflammatory mediator, platelet-activating factor (PAF), on vascular permeability in airways (and other tissues) of guinea pigs by measuring extravasation of circulating Evans blue dye. PAF caused a dose-dependent increase in vascular permeability. At 1 ng/kg iv, PAF caused an increase in Evans blue extravasation of 220% (P less than 0.05) in the trachea, with the greatest effect at a dose of 100 ng/kg (858%; P less than 0.01). Histamine (150 micrograms/kg iv) caused a 320% increase over base line in the trachea and 200% in main bronchi; this effect was equivalent to that induced by 10 ng/kg PAF in the trachea and 1 ng/kg in main bronchi. The duration of effect of PAF was greatest in main bronchi (less than 10 min). Platelet depletion with a cytotoxic antibody, or the cyclooxygenase inhibitor, indomethacin, or the cyclooxygenase-lipoxygenase inhibitor, BW 7556, did not affect the vascular permeability response to PAF. The PAF-receptor antagonist, BN 52063, inhibited Evans blue extravasation in the airways in a dose-dependent manner, with complete inhibition at 5 mg/kg. Thus PAF-induced airway vascular leakage is mediated by specific receptors but not by products of arachidonic acid metabolism or by platelets. Increased airway microvascular leakage induced by PAF may lead to plasma extravasation and airway edema, factors that may contribute to the airway narrowing and hyperresponsiveness induced by PAF.

Specific pathogen-free rats were exposed to the cigarette smoke (CS) of 25 cigarettes daily for 14 days and concurrently given N-acetylcysteine (Nac) as 1% of their drinking water (average daily dose 973 mg/kg). The thickness of the epithelium was measured at four airway levels and the numbers of mucus-containing secretory cells, stained for neutral or acidic glycoprotein (NGP or AGP respectively), were counted in surface epithelium at eight airway levels. Cigarette smoke increased the thickness of the epithelium at three of the airway levels studied by between 37 and 72%. The number of secretory cells was increased at all airway levels distal to the upper trachea by between 102 and 421%. Secretory cells containing NGP were reduced in number but this was more than offset by a large increase in the number of secretory cells containing AGP at all airway levels. N-acetylcysteine inhibited CS-induced epithelial thickening. Nac also inhibited the CS-induced increase in the number of secretory cells with AGP, but had little effect on the CS-induced reduction in the number of cells with NGP. Thus, prophylactic oral N-acetylcysteine led to an overall inhibition of CS-induced mucous cell hyperplasia and epithelial hypertrophy. The results suggest a novel anti-inflammatory action for a drug with known mucolytic effects.

No abstract

1. Airway oedema resulting from increased microvascular permeability is a characteristic pathological finding of asthma. The regional effects of putative mediators involved in asthma on airway microvascular permeability have been studied. 2. The effects of histamine, leukotriene (LT) D4 and platelet-activating factor (PAF) on microvascular permeability in the nasal mucosa, larynx, trachea, main bronchi and intrapulmonary airways of the guinea pig were assessed by measuring the extravasation of intravenously administered Evans Blue dye. 3. PAF and LTD4 caused increased microvascular leakage throughout the respiratory tract, although their effects were maximal in different regions. Histamine had no significant effect on intrapulmonary airways. PAF was more potent than LTD4 and histamine at all airway levels. For example, in the trachea the doses required to cause leakage of 50% of maximal (ED50) were 10.4 nmol/kg, 138 nmol/kg and 11.2 mumol/kg, respectively, for PAF, LTD4 and histamine. 4. The effect of the three mediators was maximal 5 min after intravenous administration. Histamine, but neither LTD4 nor PAF, still caused significant leakage 30 min after administration. 5. The increased microvascular leakage induced by the mediators was inhibited by their respective specific receptor antagonists, suggesting that the effect was mediated via specific receptors. 6. Histamine, LTD4 and PAF have varying potencies in increasing microvascular permeability in the guinea-pig respiratory tract, exert their maximal effect in different regions and have varying durations of action.

1 In order to examine the role of nitric oxide (NO) on airway mucus secretion we studied the effects of the nitric oxide synthase (NOS) inhibitor L-N0-monomethyl-L-arginine (L-NMMA), a novel nitric oxide donor, (± )-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), and the NO precursor Larginine on basal mucus secretion in the ferret trachea in vitro in Ussing chambers. We also determined the effects of these agents upon secretion induced by electrical stimulation of nerves or by acetylcholine (ACh). We used 35SO4 as a mucus marker. 2 L-NMMA (0.01-1 mM) increased basal output of 35SO4-labelled macromolecules with a maximal increase above baseline of 248% at 0.1 mM L-NMMA. L-Arginine (1 mM) alone had no significant effect on basal secretion but reversed the potentiating effect of L-NMMA on basal secretion. L-NMMAinduced increases in basal mucus secretion were sustained for at least 30 min in the continuing presence of the NOS inhibitor. In contrast to the potentiating effects of L-NMMA, FK409 (100 nM) reduced basal secretion by 60% (at 1 nM and at 10 nM it was without effect). 3 Electrical stimulation (50 V, 10 Hz, 0.5 ms for 5 min) increased 35SO4 output by 174%. L-NMMA (1 and 10 mM) present during stimulation of tracheal segments resulted in significant potentiations of 214% and 116%, respectively, of the neurogenic response. The potentiated response to 10 mM L-NMMA was reversed by L-arginine (1 mM). At this dose L-arginine had no effect itself on basal secretion. In contrast to the potentiating effects of L-NMMA on neurogenic secretion, FK409 at 10 nm and 100 nM inhibited the neurogenic response by 98% and 99%. 4 At all concentrations tested, neither L-NMMA (0.01 mM-1 mM) nor FK409 (1-100 mM) had any significant effect on ACh-induced mucus secretion. 5 These observations lead us to conclude that nitric oxide, derived from constitutive NO synthase, acts as an endogenous inhibitor of both basal and neurogenic mucus secretion in ferret trachea in vitro.